Overconsumption of a maladaptive, generally, fast food commercialized diet consisting of foods that are calorie-dense, nutritionally-poor, phytochemical-depleted, highly processed and rapidly absorbable has been shown to increase systemic inflammation and reduce insulin sensitivity [1-3]. With chronic ingestion, this dietary pattern often results in metabolic syndrome (MetS) [FIG. 2], a combination of medical disorders that affects a large number of people in a clustered fashion. The metabolic syndrome, also termed “insulin resistance syndrome” is a non-diabetic accumulation of risk factors, which can lead to the development of diabetes but it is not identical with diabetes. As defined by the American Association of Clinical Endocrinology the metabolic syndrome (i.e. the Insulin Resistance Syndrome) is defined by five factors:                1. Elevated waist circumference:                    Men—greater than 40 inches (102 cm)            Women—greater than 35 inches (88 cm)                        2. Elevated triglycerides: Equal to or greater than 150 mg/dL (1.7 mmol/L)        3. Reduced HDL (“good”) cholesterol:                    Men—Less than 40 mg/dL (1.03 mmol/L)            Women—Less than 50 mg/dL (1.29 mmol/L)                        4. Elevated blood pressure: Equal to or greater than 130/85 mm Hg or use of medication for hypertension        5. Elevated fasting glucose: Equal to or greater than 100 mg/dL (5.6 mmol/L) or use of medication for hyperglycemia.The end result of MetS is to increase one's risk for cardiovascular disease and diabetes. In most cases, metabolic syndrome culminates in type 2 diabetes. The symptoms of metabolic syndrome are related to lipid and carbohydrate metabolism and include obesity, elevated triglycerides, low levels of high density lipoproteins, increased blood pressure or hypertension and increased glucose levels, but also symptoms of inflammation [4-7]. As worldwide food consumption patterns shift to the aforementioned dietary pattern, MetS is becoming a significant burden in developing nations and global prevalence is growing [8,9].        
It is widely viewed that MetS results from an increasing, perpetual state of whole body insulin resistance, which is strongly associated with dietary carbohydrate [10-12] and saturated fat [13], leading to high serum triglycerides (TG) and visceral adiposity [14-16]. Acute infusion of free fatty acids leads to the accumulation of TG in skeletal muscle and evokes whole body insulin resistance with the same temporal pattern [17-20]. Metabolites of lipid metabolism such as diacylglycerol have been shown to directly induce insulin resistance by chronically activating protein kinase C (PKC). PKC activation terminates insulin signaling, preventing crucial tyrosine phosphorylation by the insulin receptor, leading to impaired insulin signaling [15]. MetS is also associated with a state of chronic inflammation. Adipocyte leakage has recently been shown to result in the recruitment of macrophages, which envelope excess lipids, form foam cells, and release inflammatory cytokines, setting up a state of systemic, chronic inflammation [21,22]. These adipokines lead to the systemic activation of several protein kinases involved in inflammatory signal transduction, including phosphoinositide-3 kinase (P13K), glycogen synthase kinase (GSK-3) and PKC that singly or in concert cause insulin resistance in skeletal muscle and adipose tissue [23-25].
MetS is associated with severe health complications, such as increased risk of atherosclerotic cardiovascular disease [26] and represents a growing public health problem [27]. Development of the MetS is influenced by genetic as well as environmental factors [28, 29]. Cardiovascular diseases (CVD) in patients with MetS culminating by type 2 diabetes are a large and increasing health problem. Increased atherosclerotic lesions are believed to form the basis behind the high frequency of CVD in diabetes. The arterial wall in diabetes harbors not only increased amounts of atherosclerotic plaques, but also diffuse alterations present in non-atherosclerotic parts of the vessel wall. One element of the generalized alterations in the vasculature in diabetes is endothelial dysfunction [33], characterized by increased permeability [34], increased expression of pro-inflammatory molecules [35], and altered vasomotoric responses [36]. Moreover, changes in extracellular matrix components of the tunica media are present in both atherosclerotic and nonatheroscleroticparts of the arterial tree in diabetes. Increased concentrations of collagen type 4 [37], hyaluronic acid [38], osteopontin, osteoprotegerin [39], and metalloproteinases [40] have, for example, been described in conjunction with the presence of high amounts of glucosederived increased cross-linking of collagens [41]. Decreased amounts of several gene products related to apoptosis have been observed in vascular smooth muscle cells from normal appearing areas of arteries from patients with diabetes [42]. In addition, linear media calcifications occur with increased frequency among patients with glucose intolerance and diabetes and are strong predictors of CVD in these individuals [43,44]. In accordance, recent studies of non-atherosclerotic arterial alterations in animal models of type 2 diabetes and hyperglycemia demonstrated increased aortic stiffness and upregulation of matrix components [45], increased arterial calcification [46], and accumulation of glycosaminoglycan-rich material [47]. Thus, defects in several molecular pathways seem to be present in the arterial wall in patients with type 2 diabetes. These changes are likely to play important roles in the arterial response to injury and thus in the build-up of atherosclerotic plaques in diabetic patients. In the recent study it was used transcriptional profiling on well-defined non-atherosclerotic arterial samples from diabetic individuals. Using pathway and network analysis, the data display a statistically significant cluster of dysregulated genes in the arteries of diabetic patients, which is in accordance with the presence of a diffuse diabetic macroangiopathy, similar to the diabetic microangiopathy. This approach has not previously been used, but point towards dysregulated pathways related to matrix metabolism, triglyceride synthesis, inflammation, as well as insulin signaling and apoptosis. Dysregulated gene interactions and pathways in the cells of the arterial wall in diabetes may play important roles in the arterial response to injury and atherosclerosis [48].
In recent years, the contribution of oxidized fats to total energy intake has markedly increased in industrialized countries due to the rising consumption of deep-fried products [49]. In fast food restaurants, foodstuffs are typically fried in fats in fryers at temperatures close to 180° C. During the frying process, several chemical reactions occur within the frying oil resulting in the formation of a mixture of chemically distinct lipid peroxidation products [50]. Large quantities of the frying oil are absorbed into the fried food during deep-frying and therefore ingested during their consumption. Feeding experiments with animals revealed that ingestion of oxidized fats provokes a wide array of biological effects [51-53]. One of the most striking effects of oxidized fat is the induction of oxidative stress which is due to lipid hydroperoxides absorbed from the ingested oxidized fats and reactive oxygen species (ROS) generated from microsomal cytochrome P450 enzymes which are induced by oxidized fat [54-56]. Oxidative stress in animals fed oxidized fats is evident by elevated concentrations of lipid peroxidation products, reduced concentrations of exogenous and endogenous antioxidants, and a decreased ratio of reduced and oxidized glutathione in plasma and tissues [57-60].Recent studies have shown that consumption of oxidized fats leads to a reduction of tocopherol concentrations in animal tissues due to a reduced digestibility and an enhanced turnover of vitamin E [59,60]. Lipid hydroperoxide (LOOH) is a well-known marker of oxidative stress formed from unsaturated phospholipids; glycolipids and cholesterol by peroxidative reactions under oxidative stress. Oxidized low density lipoproteins (OxLDL) is besides membrane-bound cholesterol-derived hydroperoxides, the main form of LOOH responsible for the development of oxidative stress [61]. Lipid peroxides are directly involved in mediating endothelial dysfunction, by increasing the production of thromboxane A, and the expression of cell adhesion molecules in the vasculature, and also in the peripheral vasculature [62].
While studies have shown that increased body mass index (BMI) can pave the way to dementia, studies are now discovering that visceral fat's abnormal metabolic activities make it one of the most important factors where heart risk is concerned. Cholesterol and triglyceride levels generally increase. Average health consequences of excess visceral fat include:                Impacted insulin sensitivity and blood sugar utilization.        Compromised circulation.        Challenged immune system.        Increased inflammatory responses.        Compromised heart health, overall mobility and longevity.Pre-existing health conditions may be aggravated. There are significant changes in the myocardium during the development of abdominal obesity in the metabolic syndrome [FIG. 3], primarily of ischemic changes in the nature of the imbalance between the sharply increased demands for oxygen and substrates metabolism of hypertrophied cardiomyocytes, and reduced levels of blood supply. Marked interstitial sclerosis and fatty infiltration of the interstitium of myocardium and impede the diffusion of oxygen and substrates of a few capillaries in the working myocardial cells. Increasing energy needs for the cardiomyocytes entails the adaptive hyperplasia of mitochondria. Marked compensatory changes in organelle responsible for calcium metabolism and conjugation of excitation from contraction, hyperplasia, sarcoplasmic reticulum, increases the surface of T-system. However, hypertrophy of cardiomyocytes increases the discrepancy between the mass of muscle fibers and the deficit in the microcirculation, which leads to the breakdown of adaptive mechanisms. Thus, there are destructive and atrophic processes in place. Occurred depression of respiratory function of mitochondria, decreased the binding and capture of Ca2 +, the accumulation of triglycerides, inhibition of fatty acid oxidation, lipid peroxidation, accumulation of products extended peroxidation in the myocardium. Accumulation of triglycerides and fatty acids in the heart muscle cells leads to disruption of the contractile function of myofibrils, followed by their atrophy and death [63].        
Ventricular myocytes contain about 75% of the protein mass of myocardium and provide a significant contribution to the “cardiac hypertrophy”. Along with the myocytes in the myocardium, there are other active cells—fibroblasts, smooth muscle cells vascular endothelial cells. All of them are also involved in the development of myocardial pathology, as may produce local factors that can stimulate myocyte hypertrophy. Among these factors can result in endothelin, norepinephrine, angiotensin II, secreted by fibroblasts, tumor necrosis factor, growth factors, etc [63]. Very important question of how mechanical stress is converted into biochemical signals. Suggest that mechanical stress directly alters the conformation of functional proteins or activates enzymes such as phospholipase. Myocyte hypertrophy is an accumulation of proteins (in particular accelerates the synthesis of myofibrillar proteins (e.g., myosin), and ribosomes). The overall rate of protein synthesis is defined as its “effectiveness” (the speed with which the synthesized nascent peptide chains on the ribosome) and its volume (the relative number of ribosomes). The increase in protein mass in cardiac hypertrophy is a result of increasing the volume and efficiency, and synthesis. It is known that myocytes forming arterial and ventricular able to hypertrophic growth. The experiments showed that cardiac myocytes retain the ability to synthesize DNA and re-enter the cell cycle of development. That growth is explained by myocyte hypertrophy, infarction, which is expressed in increasing the mass of the ventricles. Ventricular fibrillation is the form of arrhythmia. The overwhelming majority of sudden cardiac deaths from corollary disease are thought to be from ventricular fibrillation. Atrial Fibrillation (AF), one of the most common kinds of arrhythmias, is responsible for at least 15 to 20 percent of all ischemic strokes [63].
Metabolic syndrome (MetS) is the coexistence of hyperglycaemia, hypertension, dyslipidemia and obesity. Therefore cardiovascular diseases such as coronary heart diseases and stroke are more prevalent among patients with metabolic syndrome [64]. MetS increases the risk of premature death [30, 31, 32], therefore, effective and affordable strategies to assist to reduce cardiometabolic risk factors and control the syndrome would benefit the population at risk. As such, an important aspect to consider in dietary recommendations for MetS is the incorporation of diverse, targeted biologically-active nutritional compounds to address the multiple underlying mechanisms of MetS.
E-148-2010/0 claims hesperidin is a flavonoid compound found in citrus fruits for administration of oral hesperidin to patients with metabolic syndrome to attenuate biomarkers of inflammation and improve blood vessel relaxation, lipid cholesterol profiles, and insulin sensitivity. Thus, claims hesperidin and its active aglycone form, hesperetin, which may be effective agents for the treatment of diabetes, obesity, metabolic syndrome, dyslipidemias, and their cardiovascular complications including hypertension, atherosclerosis, coronary heart disease, and stroke.
US 2011/0306575 A1 provides a method for using processed cellulose for lowering values of risk factor measurements for such diseases as arteriosclerotic cardiovascular disease and diabetes.
EP 1 350 516 B1 claims a hydrophobic licorice extract, and extracts from turmeric, clove and cinnamon for the use of treating metabolic syndrome as well as associated diseases like visceral obesity and diabetes mellitus. The activity of the extracts is measured in reference to troglitazone and pioglitazone.
U.S. Pat. No. 7,202,222 B2 claims dihydroquercetin and root-derived aralosides for the use of treating obesity and fat loss promotion.
CA 2 526 589 A1 describes ligands of PPAR-gamma, in particular glabrene, glabridine, glabrol and their derivatives, and glitazones. These compounds are mentioned in connection with the multiple risk factor syndrome, another name of the metabolic syndrome, which is related to insulin resistance and can be treated with PPAR-gamma ligands. Also described is a licorice extract for the treatment of metabolic syndrome.
JP 2005/097216 mentions dehydrodieugenol A and B, magnolol, oleanic acid and betulic acid as PPAR-gamma ligands that are useful for preventing or ameliorating metabolic syndrome.
U.S. Pat. No. 6,495,173 B1 claims a red yeast rice, coenzyme Q10, and chromium with or without inositol hexanicotinate, selenium and mixed tocoferols to reduce or control blood cholesterol, triglycerides, low density lipoproteins, to reduce arterial plaque build-up, atherosclerosis in mammal.
US 2010/0291050 A1 claims a nutritional composition for reducing oxidative damage and lipid peroxidation in humans, where is the compositions comprise adaptogens such as astragalus root, ashwagandha root, cordyceps, holy basil leaf, maca root, reishi mashrooms, schizandra, and suma root; superfruits comprising acerola, camu-camu, pomegranate, bilberry, blueberry, Goji berries, Acai, maitake, citrus bioflavonoids, rose hips and Gingko biloba.
McCue, Patrick et al. (Asia Pacific Journal of Clinical Nutrition 13(4) (2004):401-408) also describe the efficacy of extracts of oregano and specific compounds, e.g. rosmarinic acid and Quercetin on the activity of a-amylase through the inhibition of the enzyme. Symptoms like hyperglycaemia, type 2 diabetes and prediabetes impaired glucose tolerance could be treated.
The essential nutritional novel compounds have been used individually to help in various health pathologies and disorders, and thus have a long history of safe use in humans. However, neither of these compounds has been used to assist in reducing and controlling cardiometabolic risk factors in mammals, and in particular in humans. Thus, there exists a need for nutritional novel compounds to be used as nutraceutical agents for the assistance to prevent and/or manage metabolic syndrome and cardiovascular disorders and related diseases, particularly, cholesterol- or lipid-related disorders, such as, for example, atherosclerosis.
Dihydroquercetin (taxifolin) is the flavonoid compound having molecule structure is based on C6—C3—C6 skeleton consisting of two aromatic rings joined by a three carbon link with the absence of the C2—C3 double bond and have two chiral carbon atoms in position 2 and 3 [FIG. 4]. The A ring of the flavonoid structure being acetate derived (3×C2) and the C and 13 rings originating from cinnamic acid derivatives (phenylpropanoid pathway). Consequently, the B-ring can be either in the (2S)- or (2R)-configuration. The C-3 atom of dihydroflavonol Dihydroquercetin (taxifolin) bears both a hydrogen atom and a hydroxyl group, and is therefore an additional center of asymmetry [73]. Thus, four stereoisomers are possible for each dihydroflavonol structure, (2R,3R), (2R,3S), (2S,3R), and (2S,3S). All four configurations have been found in naturally occurring dihydroflavonols, but the (2R,3R)-configuration is by far the most common. Conifer wood species, especially those from the family of Pinaceae are considered rich sources of flavonoid Dihydroquercetin (taxifolin) [65-72].
Arabinogalactans are class of long, densely branched low and high-molecular polysaccharides MW: 3,000-120,000 [FIG. 5]. The molecular structures of water-soluble arabinogalactans from different hardwood species have been intensively investigated. Arabinogalactans consist of a main chain of b-D-(1fi3)-galactopyranose units (b-D-(1fi3)-Galp) where most of the main-chain units carry a side chain on C-6 [fi3,6)-Galp-(1fi]. Almost half of these side chains are b-D-(1fi6)-Galp dimers, and about a quarter are single Galp units. The rest contain three or more units. Arabinose is present both in the pyranose (Arap) and furanose (Araf) forms, attached to the side chains as arabinobiosyl groups [b-L-Arap-(1fi3)-LAraf-(1fi] or as terminal a-L-Araf e.g. a single L-arabinofuranose unit or 3-O-(β-L-arabinopyranosyl)-α-L-arabinofuranosyl units [74-77].
After screening of a large number of vegetable by-products, were obtained numerous dietary fibers with exceptional biological antioxidant capacity from fruits and other vegetable materials. These fibers combine in a single material the physiological effects of both dietary fiber and antioxidants [78]. Dietary fiber arabinogalactan from hardwoods, mainly from Larix dahurica (Larix gmelinii), Larix sibirica, Larix sukaczewii larch wood species, i.e. larch arabinogalactan can be defined as a fiber containing significant amounts of natural antioxidants, mainly Dihydroquercetin (taxifolin) associated naturally to the fiber matrix with the following specific characteristics: 1. Dietary fiber content, higher than 70% dry matter basis. 2. One gram of dietary fiber larch arabinogalactan should have a capacity to inhibit lipid oxidation equivalent to, at least, 1,000 umol TE/gram basing on ORAC value. 3. One gram of dietary fiber larch arabinogalactan should have a capacity of Cell-based Antioxidant. Protection (CAP-e) to protect live cells from oxidative damage to, at least 6 CAP-e units per gram, where the CAP-e value is in Gallic Acid Equivalent (GAE) units [FIG. 7]. 4. The antioxidant capacity possess an intrinsic property, derived from natural constituents of the material (soluble in digestive fluids) not by added antioxidants or by previous chemical or enzymatic treatments [FIG. 8]. The table in FIG. 8 shows the results obtained in vitro, and presented in the following order: the antioxidant capacities as determined by the FRAP, TEAC, and deoxyribose assays. All the samples investigated were found to exhibit antioxidative properties. The FRAP assay takes advantage of electron-transfer reactions. Herein, a ferric salt, Fe(III)(TPTZ)2Cl3 (TPTZ=2,4,6-tripyridyl-s-triazine), is used as an oxidant. The reaction detects species with redox potentials <0.7 V [the redox potential of Fe(III)(TPTZ)2], so FRAP is a reasonable screen for the ability to maintain redox status in cells or tissues. Reducing power appears to be related to the degree of hydroxylation and extent of conjugation in flavonoids. However, FRAP actually measures only the reducing capability based on ferric iron, which is not relevant to antioxidant activity mechanistically and physiologically. The TEAC assay is based on the formation of ferrylmyoglobin radical (from reaction of metmyoglobin with H2O2), which may then react with ABTS [2,2′-azinobis(3-ethylbenzothiazoline-6)-sulfonic acid] to produce the ABTS*+ radical. ABTS*+ is intensively colored, and AC is measured as the ability of the test species to decrease the color by reacting directly with the ABTS*+ radical. Results of test species are expressed relative to Trolox. Deoxyribose assays: Hydroxyl radicals, generated by reaction of an iron-EDTA complex with H2O2 in the presence of ascorbic acid, attack deoxyribose to form products that, upon heating with thiobarbituric acid at low pH, yield a pink chromogen. Added hydroxyl radical “scavengers” compete with deoxyribose for the hydroxyl radicals produced and diminish chromogen formation. A rate constant for reaction of the scavenger with hydroxyl radical can be deduced from the inhibition of color formation. For a wide range of compounds, rate constants obtained in this way are similar to those determined by pulse radiolysis. It is suggested that the deoxyribose assay is a simple and cheap alternative to pulse radiolysis for determination of rate constants for reaction of most biological molecules with hydroxyl radicals.
Dihydroquercetin (taxifolin) possess superior antioxidant activity [FIG. 8] to suppress affects of free radicals [79-85]. Dihydroquercetin (taxifolin) can, penetrate the human erythrocytes easily and protect from oxidative damage [FIGS. 6-7]. Protocol for the empirical studies illustrated in FIG. 6 can be described as follows:                For each test product, 0.4 g was mixed with 4 mL 0.9% saline at physiological pH. Products were mixed by inversion and then vortexed. Solids were removed by centrifugation at 2400 rpm for 10 minutes. The supernatant of the products was removed and then filtered for use in the CAP-e assay. Red blood cells were treated in duplicate with serial dilutions of the test products. Negative controls (untreated red blood cells) and positive controls (red blood cells treated with oxidizing agent) were performed in hexaplicate. The antioxidants not able to enter the cells were removed by centrifugation and aspiration of supernatant above the cell pellet. The cells were exposed to oxidative damage by addition of the peroxyl free-radical generator AAPH. Using the indicator dye DCF-DA, which becomes fluorescent as a result of oxidative damage, the degree of antioxidant damage was recorded by measuring the fluorescence intensity of each test sample. The inhibition of oxidative damage was calculated as the reduced fluorescence intensity of product-treated cells, compared to cells treated only with the oxidizing agent. The CAP-e value reflects the IC50 dose of the test product, i.e. the dose that provided 50% inhibition of oxidative damage. This is then compared to the IC50 dose of the known antioxidant Gallic Acid.Protocol for the empirical studies illustrated in FIG. 7 can be described as follows:        For each test product, 0.3 g was mixed with 3 mL 0.9% saline at physiological pH. Test products were mixed by inversion and then vortexed. After 15 minutes, solids were removed by centrifugation at 2400 rpm for 10 minutes. The supernatant of the product was removed and then filtered for use in the CAP-e assay. Red blood cells were treated in duplicate with serial dilutions of the test products. Samples of untreated red blood cells (negative controls) and samples of red blood cells treated with oxidizing agent but not with an antioxidant-containing test products (positive controls) were prepared in hexaplicate. The antioxidants not able to enter the cells were removed by centrifugation and aspiration of supernatant above the cell pellet. The cells were exposed to oxidative damage by addition of the peroxyl free-radical generator AAPH. Using the indicator dye DCF-DA, which becomes fluorescent as a result of oxidative damage, the degree of antioxidant damage was recorded by measuring the fluorescence intensity of each test sample. The inhibition of oxidative damage was calculated as the reduced fluorescence intensity of product-treated cells, compared to cells treated only with the oxidizing agent. The CAP-e value reflects the IC50 dose of the test product, i.e. the dose that provided 50% inhibition of oxidative damage. This is then compared to the IC50 dose of the known antioxidant Gallic Acid.        
Erythrocytes supplemented with Dihydroquercetin (taxifolin) exhibited high resistance against the oxdative stress and haemolysis produced by phenylhydrazine and the lysis induced by osmotic shock. This suggests that Dihydroquercetin (taxifolin) may act by increasing the stability of the erythrocyte membrane. Pre-incubation of RBCs with water-soluble Dihydroquercetin (taxifolin) for 30 min significantly reduced the peroxyl radical (AAPH)-induced hemolysis to 32.5±5.6%. Dihydroquercetin (taxifolin) was highly effective in reducing phospholipase C-induced hemolysis (45.4±10.0% versus vehicle 75.7±5.2%, P<0.001). Dihydroquercetin (taxifolin) showed a greater potency of inhibiting xanthine-oxidase-dependent superoxide generation (EC50: 17.4±3.6 μM vs 70.8±19.3 μM, P<0.001).
Dihydroquercetin (taxifolin) can modulate the expression of several genes, including those coding for detoxification enzymes, cell cycle regulatory proteins, growth factors. and DNA repair proteins. Dihydroquercetin (taxifolin) significantly activates Antioxidant Response Element. ARE (Antioxidant Response Element) in the promoter region of the human NQO1 gene contains AP-1 or AP-1-like DNA binding sites, and AP-1 proteins have been implicated in the formation or function of this and other ARE complexes. Also, ARE-binding proteins in inducing cerebral MT-1 expression and implicates MT-1 as one of the early detoxifying genes in an endogenous defense response to cerebral ischemia and reperfusion [86,87].
It have been demonstrated in numerous studies in vitro and ex vivo that Dihydroquercetin (taxifolin) inhibits lipid peroxidation, a process that often leads to atherosclerosis [88-90]. In an animal study, Dihydroquercetin (taxifolin) inhibited the peroxidation of serum and liver lipids following exposure to toxic ionizing radiation [91]. Dihydroquercetin (taxifolin)'s inhibitory effects on lipid peroxidation are enhanced by both vitamin C and vitamin E [92]. By inhibiting the oxidation of harmful low-density lipoprotein (LDL), Dihydroquercetin (taxifolin) may help prevent atherosclerosis [93].
Dihydroquercetin (taxifolin) can enhance the production of glutathione, block the production of reactive oxygen species, and prevent the late influx of calcium, all of which are activities that prevent specific events in the cell death pathway. Oxidised glutathione concentration and the oxidised/reduced glutathione ratio always increased by proinflammatory stimuli in parenchymal liver cells e.g. cytokines. These effects were significantly prevented by Dihydroquercetin (taxifolin) at all tested concentrations. Glutathione prexidase (GPx) protein level was significantly increased by Dihydroquercetin (taxifolin) in 25 and 50 μM concentrations. Dihydroquercetin (taxifolin) prevented the cell death induced by GSH (glutathione) depletion. For example, taxifolin has an EC50 of 30 μM for the protection of the RGC-5 cells from oxidative stress induced by GSH depletion but an EC50>50 μM for protection of the CNS-derived mouse HT22 cells from a similar insult [94,95].
One of the important ways in which Dihydroquercetin (taxifolin) may limit the cytokines plain is by preventing elevation of oxidized glutathione concentration and the oxidized/reduced glutathione ratio induced by inflammatory cytokines [96]. Dihydroquercetin (taxifolin) prevents calcium influx, the last step in the cell death process. By inducing the expression of antioxidant defense enzymes, it has the potential to have long-lasting effects on cellular function. This, in turn, could be highly beneficial to cells exposed to chronic oxidative stress [97]. Dihydroquercetin (taxifolin) processes benefit results in both intracellular and extracellular environments. Studies in erythrocytes, mast cells, leucocytes, macrophages and hepatocytes have shown that Dihydroquercetin (taxifolin) renders cell membranes more resistant to lesions. Dihydroquercetin (taxifolin) protects the inner walls of the blood vessels and capillaries against destructive enzymes, decay and free radical damage [98].                Partial degradation of Dihydroquercetin (taxifolin) by GIT microbiota results to the formation of 3,4-dihydroxyphenilacetic acid, another valuable antioxidant. Effect of the this microbial phenolic 3,4-dihydroxyphenylacetic acid (3,4-DHPAA), on modulation of the production of the main pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) had been yet confirmed. The production of these cytokines by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC) pre-treated with the phenolic metabolite was studied in healthy volunteers. With the exception of 4-HHA for TNF-α secretion, the dihydroxylated compound, 3,4-DHPAA significantly inhibited the secretion of these pro-inflammatory cytokines in LPS-stimulated PBMC. Mean inhibition of the secretion of TNF-α by 3,4-DHPAA was 86.4%. The concentrations of IL-6 in the culture supernatant were reduced by 92.3% with 3,4-DHPAA pre-treatment. Finally, inhibition was slightly higher for IL-1β on 97.9% by 3,4-DHPAA. These results indicate that dihydroxylated phenolic acids derived from microbial metabolism of Dihydroquercetin (taxifolin) present marked anti-inflammatory properties, providing additional information about the health benefits of dietary polyphenols and their potential value as therapeutic agents [99]. It has been shown that microbial metabolites such as 3,4-dihydroxyphenylacetic were more effective than rutin and quercetin precursors in inhibiting platelet aggregation in vitro [100].        
Dihydroquercetin (taxifolin) may have applications to assist in the management of stroke, a crippling, often fatal condition marked by a diminished supply of blood and oxygen to the brain. Studies of the effects of oxygen deprivation in rat brains demonstrated that Dihydroquercetin (taxifolin) helps to decrease the damage caused by lack of blood flow [101]. Additionally, Dihydroquercetin (taxifolin) helps to restore normal structure and electrochemical activity to nerve synapses, the junctions that allow nerve cells to transmit information [102].
Infarction in adult rat brain was induced by middle cerebral arterial occlusion (MCAO) followed by reperfusion to examine whether Dihydroquercetin (taxifolin) could reduce cerebral ischemic reperfusion (CI/R) injury. Dihydroquercetin (taxifolin) administration (0.1 and 1.0 microg/kg, i.v.) 60 min after MCAO ameliorated infarction (by 42%+/−7% and 62%+/−6%, respectively), which was accompanied by a dramatic reduction in malondialdehyde and nitrotyrosine adduct formation, two markers for oxidative tissue damage. Overproduction of reactive oxygen species (ROS) and nitric oxide (NO) via oxidative enzymes (e.g., COX-2 and iNOS) was responsible for this oxidative damage. Dihydroquercetin (taxifolin) inhibited leukocyte infiltration, and COX-2 and iNOS expressions in CI/R-injured brain. Dihydroquercetin (taxifolin) also prevented Mac-1 and ICAM-1 expression, two key counter-receptors involved in firm adhesion/transmigration of leukocytes to the endothelium, which partially accounted for the limited leukocyte infiltration. ROS, generated by leukocytes and microglial cells, activated nuclear factor-kappa B (NF-kappaB) that in turn signaled up-regulation of inflammatory proteins. NF-kappaB activity in CI/R was enhanced 2.5-fold over that of sham group and was inhibited by Dihydroquercetin (taxifolin). Production of both ROS and NO by leukocytes and microglial cells was significantly antagonized by Dihydroquercetin (taxifolin). These data suggest that amelioration of CI/R injury by Dihydroquercetin (taxifolin) may be attributed to its anti-oxidative effect, which in turn modulates NF-kappaB activation that mediates CI/R injury [103].
Dihydroquercetin (taxifolin) is known to inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis [104] and lower plasma triglycerides levels [105, 106]. It is consistent with the activity of other compounds used for the mitigating neglect effects of hypercholesteremia (e.g. statins), which reduce cholesterol and/or triglycerides levels [105]. The effects of Dihydroquercetin (taxifolin) on lipid, apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I) synthesis and secretion were determined in HepG2 cells. Pretreatment of cells with (+−)-taxifolin led to an inhibition of cholesterol synthesis in a dose-and time-dependent manner, with an 86+−3% inhibition at 200 umol observed within 24 h. As to the mechanism underlying this inhibitory effect, Dihydroquercetin (taxifolin) was shown to inhibit the activity of HMG-CoA reductase by 47+−7%. In addition, cellular cholesterol esterification, and triacylglycerol and phospholipid syntheses, were also significantly suppressed in the presence of Dihydroquercetin (taxifolin). ApoA-I and apoB synthesis and secretion were then studied by pulse-chase experiments. ApoA-I secretion was found to increase by 36+−10%. In contrast, an average reduction of 61+−8% in labeled apoB in the medium was apparent with Dihydroquercetin (taxifolin) [107]. Dihydroquercetin (taxifolin) was shown to markedly reduce apoB secretion under basal and lipid-rich conditions up to 63% at 200 micromol/L. As to the mechanism underlying this effect, was examined whether Dihydroquercetin (taxifolin) exerted its effect by limiting triglycerides (TG) availability in the microsomal lumen essential for lipoprotein assembly. Dihydroquercetin (taxifolin) was shown to inhibit microsomal TG synthesis by 37% and its subsequent transfer into the lumen (−26%). The reduction in synthesis was due to a decrease in diacylglycerol acyltransferase (DGAT) activity (−35%). The effect on DGAT activity was found to be non-competitive and non-transcriptional in nature. Both DGAT-1 and DGAT-2 mRNA expression remained essentially unchanged suggesting the point of regulation may be at the post-transcriptional level. Evidence is accumulating that microsomal triglyceride transfer protein (MTP) is also involved in determining the amount of lumenal TG available for lipoprotein assembly and secretion. Dihydroquercetin (taxifolin) was shown to inhibit this enzyme by 41%. Whether the reduction in TG accumulation in the microsomal lumen is predominantly due to DGAT and/or MTP activity remains to be addressed. In summary, Dihydroquercetin (taxifolin) reduced apoB secretion by limiting TG availability via DGAT and MTP activity [108].
The in vivo studies demonstrated improved glucose tolerance, lower insulin levels, lower triglyceride (TG) mass in tissues, lower plasma TG and cholesterol levels, and a decrease in serum ApoB levels as the results of Dihydroquercetin (taxifolin) exposure. These metabolic benefits are due at least in part to peroxisome proliferator-activated receptor (PPAR) activation that occurred like in case of Dihydroquercetin (taxifolin) supplementation. Dihydroquercetin (taxifolin) and its metabolites may exert their effect on PPAR expression indirectly by affectin protein signaling upstream of PPARa and PPARy or by direct binding activity, as well as with observed effects on protein downstreat of PPAR such as ApoA and GLUT2. Dihydroquercetin (taxifolin) supplementation of HepG2 cells resulted in an increase of PPARa expression. Results for PPARy were nearly identical to those for PPARa. The activation dosage was established up to 100 μM in mice. Dihydroquercetin (taxifolin) is associated with dose dependent increase in both PPARa and PPARy expressions [109]. DI-IQ results in the phosphorylation of the insulin receptor and IRS-1, thus enhancing insulin signaling within the cell [110,111]. Since PPARa and PPARy can be activated by phosphorylation through the insulin sensitive P13 kinase pathway, the possibility exists that PPARa and PPARy upregulation occurred as the result of insulin mimic action by Dihydroquercetin (taxifolin). PPAR activation could be occurring through epidermal growth factor inhibition (EGF). EGF and PDGF (platelet derived growth factor) both, when activated, inhibit PPARy expression through MAP kinase signaling, which in turn inhibited by Dihydroquercetin (taxifolin). The Dihydroquercetin (taxifolin) mediated PPAR response can in turn improve glucose uptake into cells, enhance insulin sensitivity, improve lipid metabolism and lipid biomarkers, reduce weight gain, and even beneficially impact endothelial function, inflammation, and other CVD risk factors. Microsomal lipid peroxidation induced by NADPH-cytochrome P-450 reductase was also inhibited by Dihydroquercetin (taxifolin). Dihydroquercetin (taxifolin) protected peroxy radical-damaged mitochondria with no effect on enzyme activity [112] In this way, Dihydroquercetin (taxifolin) has the potential to effectively support in fighting with insulin resistance, diabetes, and heart disease, which is so prelevant around the world. Dihydroquercetin (taxifolin) also stabilize blood vessels and protect against factors that cause atherosclerosis and cardiac, hepatic, and bronchio-pulmonary diseases.
It had been studied the effects of Dihydroquercetin (taxifolin) on functional activity of polymorphonuclear neutrophils from patients with non-insulin-dependent diabetes mellitus. Dihydroquercetin (taxifolin) dose-dependently suppressed generation of anion radicals and hypochlorous acid and production of malonic dialdehyde during oxidation of neutrophil membranes. Dihydroquercetin (taxifolin) decreased activities of protein kinase C and myeloperoxidase in activated polymorphonuclear neutrophils and could bind transition metals (Fe2+). These properties determine the ability of Dihydroquercetin (taxifolin) to decrease in vivo functional activity of polymorphonuclear neutrophils from patients with non-insulin-dependent diabetes mellitus [113]. Dihydroquercetin (taxifolin) has been found to help in protection against two common causes of vision loss: macular degeneration and cataract in diabetics. Macular degeneration occurs when an area of the eye's retina that is responsible for detailed vision begins to deteriorate. Dihydroquercetin (taxifolin) promotes blood flow to this region of the eye, which offers protection against vision loss. Also; by inhibiting the activity of an enzyme in the eye lens, Dihydroquercetin (taxifolin) may help to prevent cataract formation in diabetic patients [114,115].
Dihydroquercetin (taxifolin) prevented the increase in serum aspartate and alanine aminotransferase activities due to the inflammatory reaction and stimulated liver ATP phosphohydrolase activity [116]. Dihydroquercetin (taxifolin) had been evaluated by different studies as the small-molecule regulator of signalling cascades as promising anti-inflammatory agent with biological targets such as COX-2, and related pro-inflammatory mediators (cytokines and chemokines, interleukins [ILs], tumour necrosis factor [TNF]-α, migration inhibition factor [MIF], interferon [IFN]-γ and matrix metalloproteinases [MMPs]) implicated in uncontrolled, destructive inflammatory reaction. Dihydroquercetin (taxifolin) was effective with relevant biological targets that include nuclear transcription factor (NF-κB), p38 mitogen-activated protein kinases (MAPK) and Janus protein tyrosine kinases and signal transducers and activators of transcription (JAK/STAT) signalling pathways has received growing attention [117-119]. Dihydroquercetin (taxifolin) had a significant inhibitory effect on the production of cytokines, formation of ROS and NO and change in intracellular Ca2+ levels in dendritic cells of bone marrow and spleen [120]. Dihydroquercetin (taxifolin) was attributed to its inhibitory effects on tyrosinase enzymatic activity, despite its effects on increasing tyrosinase protein levels [121].
Studies indicate that dihydroquercetin is highly safe and efficacious. In fact, research suggests that dihydroquercetin is even safer than its nutritional cousin, quercetin [122,123]. No toxic effects were observed in rats that were treated with high levels of dihydroquercetin for long periods of time [124-131].
Digestive disorders are very common and affect a great number of the population. The typical American diet, which is low in fiber and high in protein and carbohydrate, is a factor in the prevalence of these digestive disorders. Low levels of short-chain fatty acids and elevated levels of ammonia are associated with this type of diet. Intake of fiber, particularly Larch Arabinogalactan, has been shown to be supportive in combating the detrimental effects caused by poor diet. Larch Arabinogalactan has been shown to increase short-chain fatty acids, decrease colonic ammonia levels, increase the numbers of beneficial bacteria in the colon, as well as improve the immune response. These favorable effects of Larch Arabinogalactan have a positive modulation of many of these too-common intestinal factors [132].
Intestinal tracts are exposed to many substances—from antibiotics to protozoal parasites to sugary, processed foods—that create an unfavorable atmosphere in the colon. The result can be constipation, diarrhea, candidiasis, parasitical infections and other conditions attributable to poor colon health. Colon cleansing is an important way to minimize the digestive tract's exposure to the multitude of micro-organisms encountered daily. Yet, relatively speaking, a properly functioning colon is actually quite clean compared to one that is filled with toxic substances, parasites, and pathogenic yeasts, fungi, and bacteria.
Larch Arabinogalactan is also believed to act as a prebiotic; it stimulates the colonic growth of such bacteria as bifid bacteria and lactobacilli that confer certain health benefits. Ingestion of Larch Arabinogalactan has a significant effect on enhancing beneficial gut microflora, specifically increasing anaerobes such as Lactobacillus. 
Short chain fatty acids, primarily acetate, propionate, and butyrate, are produced in the colon by fermentation of dietary carbohydrates, particularly from degradation-resistant starches and dietary fiber, play an important role in intestinal health. These acids are the principal energy source for the colonic epithelial cells. The non-absorbed fiber of Arabinogalactan is easily fermented by the distal gut microflora, resulting in an elevated production of short-chain fatty acids, primarily butyrate, and, to a lesser extent, propionate.
Ammonia is produced as a by-product in the colon by bacterial fermentation of protein and other nitrogen-containing substances. Research indicates that ammonia levels as low as 5 mmol/L can have detrimental effects on epithelial cells that line the colon. The toxicity of ammonia toward colonic epithelial cells can lead to cell destruction and increased turnover of these cells.
Many clinicians use prebiotics as a supplemental support for intestinal conditions including diverticulosis, leaky-gut, irritable bowel syndrome, as well as inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. Studies have shown that Larch Arabinogalactan consumption reduces intestinal ammonia generation [132]. Since even low ammonia levels can have damaging effects on intestinal colonic cells, Larch Arabinogalactan can be supportive to patients who are unable to detoxify ammonia.
The relationship between dietary fiber intake and cardiometabolic risk factors has been noted in many studies [133, 134]. The use of soluble fibers is one of the diet strategies shown to decrease serum cholesterol concentrations [135]. Based on data from controlled clinical trials it has been estimated that daily intake of 2-10 grams, per day (g/d) of soluble fiber significantly decreases total and LDL-cholesterol [136].
Besides a hypolipidemic effect, there is a growing body of literature suggesting that soluble fibers also lower blood pressure [137] and cardiovascular disease (CVD) risk in general [138,139]. Soluble, dietary fiber consumption has been inversely related to hypertension [140] and diastolic blood pressure [141.] and several intervention studies of soluble fibers have reported blood pressure reductions in both hypertensive and normotensive individuals [142-145]. However, the practical utility of soluble fibers as hypocholesterolemic and hypotensive agents is often limited by the lower gastrointestinal side effects associated with increased consumption and related to their fermentability. Many trials have investigated the effects of soluble, dietary fiber on cardiometabolic risk factors. For example, several trials have been conducted to test the effectiveness of various soluble, dietary fibers to modify cardiovascular disease. Results, however, have been highly variable. Furthermore, despite multiple theories of the mechanism by which soluble fiber acts to decrease serum cholesterol levels and attenuate glucose and insulin response, it is still unclear how such fibers exert their effects.
Dietary fiber arabinogalactan from hardwoods, mainly from larch wood species, i.e. larch arabinogalactan can be defined as a fiber containing significant amounts of natural antioxidants, mainly Dihydroquercetin (taxifolin) [FIGS. 7-8] associated naturally to the fiber matrix with the following specific characteristics: 1. Dietary fiber content, higher than 70% dry matter basis. 2. One gram of dietary fiber larch arabinogalactan should have a capacity to inhibit lipid oxidation equivalent to, at least, 1,000 umol TE/gram basing on ORAC value. 3. One gram of dietary fiber larch arabinogalactan should have a capacity of Cell-based Antioxidant Protection (CAP-e) to protect live cells from oxidative damage to, at least 6 CAP-e units per gram, where the CAP-e value is in Gallic Acid Equivalent (GAE) units. 4. The antioxidant capacity possess an intrinsic property, derived from natural constituents of the material (soluble in digestive fluids) not by added antioxidants or by previous chemical or enzymatic treatments.
Except soluble dietary fiber larch arabinogalactan, the practical use of soluble fibers is limited by the untoward side effects associated with increased consumption. Studies have reported gastrointestinal discomfort, including flatulence, bloating, nausea, feeling of fullness, and loose stools. In addition, many soluble fibers have marginal palatability (e.g., guar gum) or are difficult to consume frequently because of their energy content (e.g., oatmeal). These issues limit the quantity of soluble fiber a person can consume, and thus, limit the amount of benefit to be experienced. However, soluble dietary fiber larch arabinogalactan and larch arabinogalactan consisting naturally with flavonoid Dihydroquercetin (taxifolin) possess minimum discomfort for consumers with mentioned side effects, same time delivers effectiveness to attenuate cardiometabolic risk factors. It has been now discovered that nutritional compounds Dihydroquercetin (taxifolin), Arabinogalactan, and Arabinogalactan combined with Dihydroquercetin (taxifolin) are effective to reduce and control cardiometabolic risk factors associated with metabolic syndrome and hypercholesterolemia in a mammal, specifically a human, resulting in the enhancement of metabolism, reducing or control levels of cholesterol and triglycerides, reducing oxidative damage in humans and resultant health benefits.